Multiple Myeloma (MM) is a deadly plasma cell malignancy. Treatment advances have improved clinical outcomes over the past decade, but the disease remains incurable, thus creating a need for new and innovative treatment options. The MM drug pipeline includes several proteasome inhibitors and immunomodulatory agents, and other classes of agents that target signaling pathways or stromal elements in the MM tumor microenvironment. While these agents may effectively target the surrounding biology of MM, they fail to block the underlying genetic drivers of the disease, a challenging task given the heterogeneity of MM. We have developed a highly innovative therapeutic strategy that targets a singular, key genetic mechanism that is responsible for the transformation of normal plasma cells - ImmunoGlobulin Heavy chain (IgH) gene translocations. We have the ability to pharmacologically block the activity of IgH gene enhancers, which are the critical regulatory elements within the IgH locus, an effect that down-regulates MM oncogenes and inhibits the growth and survival of MM cells. IgH enhancers are ideal therapeutics in MM, as they: (1) are a central and unifying element in the pathogenesis of a heterogeneous disease, (2) are responsible for inducing the aberrant transcription of oncogenes that are erroneously translocated into the IgH gene locus, and (3) are only active in B and plasma cells, making them highly specific to cancers that originate from this tissue compartment. The overall objective of the proposed phase I STTR research proposal is to demonstrate the proof-of-concept for the targeted therapeutic strategy using cellular and animal models of MM. Our first aim is to evaluate the in vitro activity (potency, efficacy, and off-target toxicity) of 4 chemotype inhibitos of IgH gene enhancers that were discovered in the preliminary discovery phase of the project. Compounds were discovered using a molecular imaging platform that we developed and optimized for high throughput drug screening. In our second aim, the top 1 or 2 compounds will be evaluated in an established mouse model of MM. These are critical development steps that will demonstrate the scientific merit and feasibility of the therapeutic approach, and will identif the strongest lead compounds for further development in subsequent R&D phases of the project. Inhibitors of IgH gene enhancers have broad-reaching potential given the high incidence of IgH gene translocations in not just MM but nearly all B and plasma cell malignancies, including non-Hodgkin lymphoma, plasma cell leukemia, amyloidosis, and others. In our estimation, this therapeutics could have an impact on more than 100,000 new cancer cases that are diagnosed each year in the U.S.